Imidazol-1-yl and pyridin-3-yl derivatives of 4-phenyl-1,4-dihydropyridines combining Ca super(2+) antagonism and thromboxane A sub(2) synthase inhibition

• Published in: Journal of medicinal chemistry 1993-01, Vol.36 (20), p.2964-2972
• Main Authors: Cozzi, P, Carganico, G, Fusar, D, Grossoni, M, Menichincheri, M, Pinciroli, V, Tonani, R, Vaghi, F, Salvati, P
• Format: Article
• Language: English
• ISSN: 0022-2623

A series of derivatives of 4-phenyl-1,4-dihydropyridine bearing imidazol-1-yl or pyridin-3-yl moieties on the phenyl ring were synthesized with the aim of combining Ca super(2+) antagonism and thromboxane A sub(2) (TxA sub(2)) synthase inhibition in the same molecule. Some of these compounds showed significant combined Ca super(2+) antagonism and TxA sub(2) synthase inhibition in vitro, while others showed only one single activity. Structural requirements for significant single or combined activities are discussed. Theoretical conformational analysis, by molecular mechanics and semiempirical AM1 calculations, was performed for 1,4-dihydro-2,6-dimethyl 4-[3-(1H-imidazol-1-yl)phenyl] 3,5-pyridinedicarbo xylic acid, diethyl ester (FCE 24265) and two close congeners. FCE 24265, which inhibited TxB sub(2) production in rat whole blood with IC sub(50) = 1.7 x 10 super(-7) M and antagonized K super(+) induced contraction in guinea pig aorta with IC sub(50) = 6.0 x 10 super(-8) M, was selected for further pharmacological evaluation. Our results show that this compound is less potent than nifedipine both in vitro and in vivo yet presents a favorable profile in vivo, lowering blood pressure without inducing reflex tachycardia. Moreover, its additional potent and selective TxA sub(2) synthase inhibitory activity makes this compound an interesting pharmacologic tool in pathologies where both enhanced TxA sub(2) synthesis and cellular Ca super(2+) overload are involved.